Epithelial layer jamming in breast cancer cell migration

乳腺癌细胞迁移中的上皮层干扰

• 批准号: 9148220
• 负责人: Jeffrey J Fredberg
• 金额: $ 61.41万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148220
• 关键词: Adhesions; Adhesives; Affect; Blood Circulation; Breast Cancer Cell; Breast Cancer cell line; Breast Epithelial Cells; Cell Adhesion; Cell Line; Cell Shape; Cell-Cell Adhesion; Cells; Core Facility; Crowding; Data; Development; Disease Progression; Duct (organ) structure; E-Cadherin; Environment; Epithelial; Epithelial Cells; Freezing; Health; Heterogeneity; Individual; Laboratories; Lead; Link; Liquid substance; MCF10A cells; Maintenance; Malignant - descriptor; Mammary Neoplasms; Measures; Mechanics; Motion; Neoplasm Circulating Cells; Non-Malignant; Organogenesis; Patients; Pattern Formation; Phase; Phenotype; Physics; Play; Population; Property; Proteins; Role; Shapes; Side; Small Interfering RNA; Solid; Speed; Staging; Testing; Therapeutic Intervention; Thinking; Traction; Tumor Cell Migration; cancer cell; cancer prevention; cancer stem cell; cancer therapy; cell motility; design; epithelial to mesenchymal transition; indexing; insight; kinematics; knock-down; lens; malignant breast neoplasm; migration; monolayer; movie; neoplastic cell; novel; novel strategies; oncology; physical science; preconditioning; research study; stem; stemness; theories; tumor; tumor progression

 DESCRIPTION (provided by applicant): Theoretical advances and experimental evidence from our laboratories now establish that migration of the constituent cell within the non-malignant epithelial cellular layer becomes dominated by physical interactions with nearest neighbors in a manner that is consistent with cell jamming. With changes of cellular crowding, cell-cell adhesion, or cooperative cellular propulsion, the confluent cellular collective can undergo a transition from a solid-like jammed phase in which cells become virtually frozen in place, to a fluid-like, unjammed phase in which cells readily exchange places and flow. The theory of critical scaling exponents predicts that the transition from solid-like jammed to fluid-lke unjammed phases is promoted by increased cell adhesive forces and linked to changes in cell shape. This theoretical prediction comprises our central hypothesis. Importantly, predictions from this theory are paradoxical to classical thinking but are borne out nevertheless by our preliminary data. Hence, this theory of cell jamming brings with it a new mechanism and a new physical picture of breast cancer cell migration. To test this theory, in Aim 1 we will characteriz jamming dynamics in a selected subset of the 9 breast cancer cell lines comprising the Bioresource Core Facility of the Physical Sciences-Oncology Network. In Aim 2 we will assess how cell-cell adhesion affects jamming with a specific focus on the changes in cellular adhesion that occur during the epithelial-to-mesenchymal transition (EMT). In Aim 3 we will investigate how the presence of cancer stem cells influence cellular jamming and collective motion. Impact: A key step in cancer progression is collective tumor cell migration, but how each individual cell coordinates its migration with that of immediate neighbors has defied mechanistic understanding. Here we propose experiments designed to unveil basic physics of collective cellular migration in early stages of tumor progression. Data derived from a comprehensive suite of experimental probes -cellular motions, traction forces, intercellular forces1,2,4,7-9 and cellular shapes- will be critically viewed through the lens of a novel theory of critical scaling.13,14 This theory of cell jamming is mechanistic, non-trivial, and counterintuitive. If supported by our data, it will not represent an incremental advance. Rather, it may provide important new insights concerning the physics of cancer progression, and, because its predictions are counterintuitive and paradoxical, it may lead to novel strategies for cancer treatment or prevention.

 描述（由申请人提供）：我们实验室的理论进展和实验证据现在证实，非恶性上皮细胞层内的组成细胞的迁移以与细胞干扰一致的方式由与最近邻居的物理相互作用主导。随着细胞拥挤、细胞间粘附或细胞协作推进的变化，汇合的细胞集体可以经历从细胞几乎冻结在原地的固体状堵塞阶段转变为细胞容易交换位置和流动的流体状未堵塞阶段。临界尺度指数理论预测，细胞粘附力的增加会促进从固体状堵塞相到流体状未堵塞相的转变，并且与细胞形状的变化有关。这一理论预测构成了我们的中心假设。重要的是，该理论的预测与经典思维相悖，但我们的初步数据证实了这一点。因此，这种细胞干扰理论带来了乳腺癌细胞迁移的新机制和新物理图景。为了测试这一理论，在目标 1 中，我们将表征构成物理科学-肿瘤学网络生物资源核心设施的 9 种乳腺癌细胞系的选定子集中的干扰动态。在目标 2 中，我们将评估细胞间粘附如何影响干扰，特别关注上皮间质转化 (EMT) 期间发生的细胞粘附变化。在目标 3 中，我们将研究癌症干细胞的存在如何影响细胞干扰和集体运动。影响：癌症进展的一个关键步骤是肿瘤细胞的集体迁移，但每个单独的细胞如何与邻近的细胞协调其迁移，尚无法理解其机制。在这里，我们提出了旨在揭示肿瘤进展早期阶段细胞集体迁移的基本物理原理的实验。从一整套实验探针（细胞运动、牵引力、细胞间力 1,2,4,7-9 和细胞形状）中获得的数据将通过一种新颖的临界缩放理论的镜头进行批判性地观察。13,14 这种细胞干扰理论是机械性的、重要的且违反直觉的。如果我们的数据支持，它不会代表增量进步。相反，它可能提供有关癌症进展物理学的重要新见解，并且由于其预测是违反直觉和矛盾的，因此它可能会带来癌症治疗或预防的新策略。